Genomic analyses have molecular classified breast cancers into several subtypes, including two derived from estrogen receptor (ER)-positive tumors (luminal A and B) and two derived from ER-negative tumors (basal-like and HER2-positive). Identification and pre-selection of breast cancer patients with hormone receptor-positive or gene amplifications, such as HER2, has translated into more personalized therapy with significant improvements in patient survival. In contrast, triple-negative breast cancers, tumors that are negative for estrogen and progesterone receptor expression and HER2 gene amplification, have a distinct gene expression profile, are molecularly classified as basal-like, exhibit a poor overall prognosis and have a high relapse rate in those patients that do not respond to chemotherapy. There is a major need to better understand the molecular basis of this type of breast cancer as well as develop new therapeutic strategies against it. The immediate goal of the studies proposed is to identify and validate druggable gene targets that regulate survival and drug sensitivity of triple-negative breast cancers. Loss-of function screening can identify molecular pathways involved in the survival and drug sensitivity of tumor cells. We conducted a pilot loss-of-function screen to determine the feasibility of identifying candidate druggable gene targets for triple-negative breast cancer. Based on preliminary data, we hypothesize that gene products (targets) involved in proliferation and survival of triple-negative breast cancers as well as targets that enhance chemo-sensitivity of these cancer cells can be identified and validated. Two aims are proposed to test this hypothesis. In the first aim, a loss-of-function screen will be performed using a druggable genome siRNA library to identify gene targets required for the proliferation and survival of triple-negative breast cancer cells as well as those that sensitize the cells to taxol or cisplatin. In Aim 2 molecular drug targets will be validated and analyzed to determine the role the gene targets play in cell proliferation, survival, and tumorigenesis and if they can serve as markers of drug response in triple-negative tumors. Candidate gene targets and associated pharmacological inhibitors of select gene products and pathways will be validated and tested in combination with taxol and/or cisplatin using a panel of triple-negative tumorigenesis and sensitivity to various drugs. Also, candidate targets will be assessed for their use as potential markers of response to treatment of patients with triple-negative disease. PUBLIC HEALTH RELEVANCE: Discoveries from the proposed research will inform future clinical trials to investigate novel single agent and combination therapies for patients with triple-negative breast cancer.